A primary objective of this research is to further characterize the behavioral response to single and repeated administration of amphetamine and other psychomotor stimulants. These studies, in addition to providing information regarding the relationships among the various response components, will also serve to establish further the criteria for identifying the neurochemical mechanisms and systems which subserve the stimulant-induced behavioral effects. We will also continue our efforts to elucidate the mechanisms underlying the alterations in the response to repeated psychomotor stimulant administration: (1) the role of monoamine systems will be studied by characerizing the acute and chronic effects of amphetamine at various times after discrete lesions produced by the CA and 5-HT neurotoxins, 6-OHDA and 5,7-DHT, respectively. Particular attention will be directed at the time course of lesion effects since the sustained depletion of monoamines may result in alterations (e.g., compensatory adjustments) which might obscure the primary effects produced by the lesion. (2) The possible involvement of receptor alterations will be examined by (a) characterizing the behavioral response to intracerebral and systemic administration of DA and NE agonists after chronic pretreatment with amphetamine; (b) comparison of the chronic amphetamine response with the response to amphetamine after long-term pretreatment with drugs such as haloperidol and alpha-MT which are alleged to produce CA receptor supersensitivity; and (c) DA and NE receptor binding studies. (3) Our research on possible dispositional factors underlying the chronic amphetamine response will involve the use of gas chromotography/mass spectrometry techniques and isotopic variants of amphetamine; we plan to continue our studies involving the brain regional pharmacokinetics of amphetamine and the amphetamine-releasable, residual pool. The proposed studies may provide for a more complete understanding of the mechanisms involved in: (1) arousal, exploratory behavior as well as stimulus and response selection; (2) the etiology of some forms of psychosis; and (3) the therapeutic action of stimulants in clinical disorders such as the hyperactive child syndrome.